Thyroid tumor cells-fibroblasts crosstalk: role of extracellular vesicles

Abstract

Tumor-stroma crosstalk leads to a tumor-promoting microenvironment. In this milieu, extracellular vesicles (EVs) are protagonists in cell-cell communication. Despite thyroid cancer being the most common endocrine malignancy, the contribution of the tumor microenvironment to thyroid cancer progression is still largely underexplored. We focused on the role of thyroid tumor cell-fibroblast interaction and EVs as mediators of tumor-stroma interplay, in the promotion of thyroid tumor aggressiveness. Thyroid tumor (TPC-1, 8505c) or non-tumor thyroid cells (NThyOri) were co-cultured with human fibroblasts (Fb). Thyroid cell migration was investigated by the wound-healing assay and actin-network staining. Cell-CD147 expression was characterized by flow cytometry. EVs, obtained by ultracentrifugation of conditioned media (CMs), were characterized by transmission electron-microscopy and CD81 and CD147 expression. Metalloproteinases (MMPs) were evaluated by zymography in CMs. A migratory phenotype was triggered in thyroid tumor cells treated with CMs from Fb or from Fb-thyroid tumor cell co-cultures. Fb-thyroid cell co-cultures induced the secretion of proMMP9 and proMMP2 and led to a significant MMP2 activation in CMs. Fb, thyroid cells and Fb-thyroid cell co-cultures released EVs, and remarkably, EVs released by Fb-thyroid tumor cell co-cultures induced the secretion of proMMP2 and the expression of MMP2 from normal Fb. A significant CD147 expression was demonstrated in Fb-thyroid tumor cell-derived EVs. These findings reveal the role of Fb and thyroid tumor cell-Fb interaction in the promotion of a microenvironment suitable for thyroid tumor progression. Moreover, they highlight, for the first time, the role of thyroid tumor cell-Fb interaction in the production of specialized EVs.

Role of extracellular vesicles in the progression, diagnosis and treatment of thyroid cancer (Review)

“…The CD147 interaction with interstitial tumor cells promoted MMP2 secretion and activation. The Fb and TC cell co-cultured CM and EVs promoted metastasis and invasive phenotypic alterations in TC and Fb cells (52). The TC and Fb crosstalk promoted TC cells and Fb EMT and tumor progression in general.…”

Ivabradine-Stimulated Microvesicle Release Induces Cardiac Protection against Acute Myocardial Infarction

“…As mentioned above, proteolysis is a leading cause of cardiac necrosis during the onse ression of myocardial infarction. We previously found that IR induces the expression of s eolytic degrading enzymes, including matrix metalloproteinases [16], and the Extrace rix Metalloproteinase Inducer EMMPRIN (CD147, Basigin), a glycoprotein when h osylated (HG-EMMPRIN), may activate several MMPs, including MMP-9 and MMP-13 [1 Ps and EMMPRIN are usually cargo components of many MVs involved in the migrat ral cancer and epithelial cells [12][13][14][15]. We found that IR reduced the release EMM aining MVs by more than 70%, and that was reversed in response to Ivabradine (Figur e cardiac HCN4+/EMMPRIN+ MVs were found in response to Ivabradine (Figure 4B), w not change the levels of endothelial CD31+CD41-/EMMPRIN+ or p 1+/CD41+/EMMPRIN+ MVs (Figure 4C,D).…”

“…We previously found that IR induces the expression of several proteolytic degrading enzymes, including matrix metalloproteinases [16], and the Extracellular Matrix Metalloproteinase Inducer EMMPRIN (CD147, Basigin), a glycoprotein when highly-glycosylated (HG-EMMPRIN), may activate several MMPs, including MMP-9 and MMP-13 [16][17][18]. MMPs and EMMPRIN are usually cargo components of many MVs involved in the migration of several cancer and epithelial cells [12][13][14][15]. We found that IR reduced the release EMMPRIN-containing MVs by more than 70%, and that was reversed in response to Ivabradine (Figure 4A).…”

“…Among others, Extracellular Matrix Metalloproteases (MMPS), and the MMP inducer EMMPRIN, play a significant role in myocardial infarction [11]. However, MMPs and EMMPRIN are also cargo components of many MVs involved in the migration and proliferation of several cancer and epithelial cells [12][13][14][15]. We hypothesize that the better outcomes experienced by patients in response to Ivabradine could be attributed, at least in part, to its effect on MV release, preventing cardiac cell death.…”

Polyelectrolyte Complexes of Ciprofloxacin and Lidocaine Improve Wound Healing in Deep Second Degree Burns and Reduce in Vitro Ciprofloxacin Cytotoxicity in Fibroblasts

“…Ethical Committee of Hospital Nacional de Clínicas, Universidad Nacional de Córdoba41 . All experiments were performed in accordance with the guidelines and regulations of the Council for Ethical Evaluation of…”